JP2017507904A - Perfluoroalkylation of carbonyl compounds. - Google Patents

Abstract

The present invention provides a method for producing a compound comprising a perfluorinated alkyl group moiety from a carbonyl compound. Typically, this process involves contacting a carbonyl compound and a silane compound in the presence of a fluorohydrogenate ionic liquid under conditions sufficient to produce a compound containing a perfluorinated alkyl group. The silane compound contains a perfluoroalkyl group. [Selection figure] None

Description

  The present invention relates to a method for producing a compound containing a perfluoroalkyl group. In one particular embodiment, the method is catalyzed by a catalytic fluorohydrogenate ionic liquid, using perfluoroalkyltrimethylsilane as the perfluoroalkylating reagent.

  Fluorine is the element with the highest electronegativity. Due to its size and inherent electronic properties, fluorine often imparts very different (and often beneficial) properties to organic molecules (Non-Patent Document 1, Non-Patent Document 2). Typically, incorporating fluorine into a molecule causes a significant change in the physical and chemical properties of the molecule. Organofluorine compounds (ie, organic compounds having one or more fluoro substituents) include important applications in a wide variety of fields including, but not limited to, materials science, agricultural chemistry, and the pharmaceutical industry (Non-Patent Document 3).

In the past, significant research has been done to incorporate fluorinated moieties into organic molecules. Trifluoromethyltrimethylsilane (TMS-CF ₃ ) is a known trifluoromethylating reagent. The usefulness of TMS-CF ₃ has been widely demonstrated by introducing trifluoromethyl groups to convert aldehydes and ketones to trifluoromethylated alcohols. It has also been demonstrated that trifluoromethyl groups are introduced at various carbon, sulfur, phosphorus and nitrogen centers (Non-patent Documents 4 and 5).

Various fluoride sources such as tetrabutylammonium fluoride (TBAF), tetrabutylammonium triphenyldifluorosilicate (TBAT), tetramethylammonium fluoride (TMAF) or cesium fluoride can be used for various electrophiles, trifluoromethyl. It is used as a catalyst (or initiator) for the oxidization reaction (Non-patent document 5, Non-patent document 6, Non-patent document 7, Non-patent document 8, Non-patent document 9, Non-patent document 10, Non-patent document 11) . However, these initiators are expensive and sensitive to humidity. The most commonly used catalyst for trifluoromethylation using TMS-CF ₃ is tetrabutylammonium fluoride (TBAF), which usually exists as a hydrated form, such as the trihydrate. TBAF is also commercially available as a 1 M THF solution. Such a solution is typically about 5% water. Attempts to dehydrate TBAF at higher temperatures often produce HF and olefin by-products. Without being bound by any theory, it is believed that the presence of water promotes the decomposition of TMSCF ₃ to CF ₃ H, resulting in a significantly lower or undesirable reaction.

  Conventional methods for converting simple esters to the corresponding trifluoromethyl ketones are relatively slow or slow processes or often result in low yields of the desired product. The main cause of this failure is the presence of water in the catalyst (TBAF). It is believed that water interferes with the catalytic cycle by destroying important intermediates formed during the reaction.

Chambers 2004 Kirsch 2004 Liebman, Greenberg, and Dolbier 1988 Prakash and Yudin 1997 Singh and Shreeve 2000 Nelson, Owens, and Hiraldo 2001 Petrov 2000 Li, Tang, and Piccirilli 2001 Sevenard et al. 2003 Benayoud et al. 2000 Lin and Jiang 2000

  Therefore, there continues to be a need for fluorination catalysts or initiators for perfluoroalkylation reactions of organic compounds.

Some embodiments of the present invention provide a method for producing a compound comprising a fully fluorinated alkyl group moiety from a carbonyl compound. Typically, such methods involve carbonyl compounds and perfluoroalkyl groups (ie, —C _n F _{2n + 1) in} the presence of a fluorohydrogenate ionic liquid under conditions sufficient to produce compounds containing perfluorinated alkyl groups. And contacting with a silane compound containing.

  In some embodiments, the carbonyl compound is an aldehyde, ketone or ester.

  In another embodiment, the silane compound is a perfluoroalkyl (trialkyl) silane compound.

  In yet another embodiment, the fluorohydrogenate ionic liquid comprises a quaternary ammonium cation. Typically, the quaternary ammonium cation comprises a nitrogen-heteroaryl cation. In some cases, the quaternary ammonium cation comprises N-ethyl-N-methylimidazolium, N-methyl-N-propylpyrrolidinium, N-methyl-N-butylpyrrolidinium, or combinations thereof .

  In another embodiment, the amount of the fluorohydrogenate ionic liquid used in the method is less than 1 equivalent with respect to the amount of the carbonyl compound.

のシロキシ化合物を生成する方法であって、該方法が式Iのシロキシ化合物を生成するのに十分な条件下においてフルオロハイドロジェネートイオン液体の存在下にて、式：

のカルボニル化合物と、式III：

のシリル化合物とを接触させることを含み、
式中、
nは1〜30の整数であり、
R¹は水素、アルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、ハロアルキル、ヘテロアルキル、（シクロアルキル）アルキル、（ヘテロシクロアルキル）アルキル、アラルキル又はヘテロアラルキルであり、
R²は水素、アルキル又は式-OR⁴部分（式中、R⁴はアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、ハロアルキル、ヘテロアルキル、（シクロアルキル）アルキル、（ヘテロシクロアルキル）アルキル、アラルキル又はヘテロアラルキルであり、
R³はそれぞれ独立してアルキル、シクロアルキル、アリール、（シクロアルキル）アルキル又はアラルキルである、方法を提供する。 Another aspect of the invention is a compound of the formula:

In the presence of a fluorohydrogenate ionic liquid under conditions sufficient to produce a siloxy compound of formula I:

A carbonyl compound of formula III:

Contacting with a silyl compound of
Where
n is an integer from 1 to 30,
R ¹ is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, haloalkyl, heteroalkyl, (cycloalkyl) alkyl, (heterocycloalkyl) alkyl, aralkyl or heteroaralkyl;
R ² is hydrogen, alkyl, or a moiety of the formula —OR ^{4 where} R ⁴ is alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, haloalkyl, heteroalkyl, (cycloalkyl) alkyl, (heterocycloalkyl) alkyl , Aralkyl or heteroaralkyl,
Provided is a method, wherein each R ³ is independently alkyl, cycloalkyl, aryl, (cycloalkyl) alkyl or aralkyl.

のケトン化合物を生成する工程を更に含む。 In some embodiments, R ² is a moiety of the formula —OR ⁴ . In these embodiments, in some cases, the method hydrolyzes the siloxy compound of formula I above to produce the formula:

The method further includes the step of producing a ketone compound.

In still other embodiments, each R ³ is independently C ₁ -C ₆ alkyl. In these embodiments, in some cases, R ³ is methyl.

  In another embodiment, the fluorohydrogenate ionic liquid contains a quaternary ammonium cation. In these embodiments, in some cases, the quaternary ammonium cation comprises a nitrogen-heteroaryl cation. In some specific cases, the quaternary ammonium cation is N-ethyl-N-methylimidazolium, N-methyl-N-propylpyrrolidinium, N-methyl-N-butylpyrrolidinium, or combinations thereof. including.

のアルコール化合物を生成する工程を更に含む。 In other embodiments, R ² is hydrogen or alkyl. In these embodiments, in some cases, the method hydrolyzes the siloxy compound of formula I above to produce the formula:

The method further includes the step of producing an alcohol compound.

  In yet another embodiment, the amount of the fluorohydrogenate ionic liquid used in the method is less than 1 equivalent relative to the amount of the carbonyl compound of formula II. In these embodiments, in some cases, the amount of the fluorohydrogenate ionic liquid used in the method ranges from about 0.2 equivalents to 0.4 equivalents relative to the amount of the carbonyl compound of Formula II.

  In yet another embodiment, the amount of silyl compound of formula III used in the method is at least 1 equivalent relative to the amount of carbonyl compound of formula II.

It should be understood that in some embodiments, the process of the present invention is performed in the absence of any other catalyst. As used herein, unless otherwise specified, the term “absence of any other catalyst” means that any other catalyst is not a significant amount (eg, less than 0.2 equivalents, typically 0.1 Less than equivalent, often less than 0.05 equivalent, more often less than 0.01 equivalent, most often less than 0.001 equivalent). Therefore, substantially only the silane compound containing the fluorohydrogenate ionic liquid and the perfluoroalkyl group (that is, —C _n F _{2n + 1} ) is used in the reaction. It should be understood that this process may optionally include an organic solvent or a mixture of organic solvents.

Definitions “Alkyl” refers to a straight chain monovalent saturated hydrocarbon moiety having 1 to 12 carbon atoms, typically 1 to 6 or a branched monovalent saturated hydrocarbon moiety having 3 to 12 carbon atoms, usually 3 to 6. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 2-propyl, tert-butyl, pentyl and the like.

  “Alkylene” refers to a straight chain divalent saturated hydrocarbon moiety having 1 to 12 carbon atoms, typically 1 to 6 or a branched divalent saturated hydrocarbon moiety having 3 to 12 carbon atoms, usually 3 to 6 carbon atoms. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, butylene, pentylene, and the like.

“Aryl” refers to a monovalent monocyclic, bicyclic or tricyclic aromatic hydrocarbon moiety of 6 to 15 ring atoms optionally substituted with one or more substituents. When an aryl group is substituted, the aryl group is typically substituted with one, two or three substituents, often one substituent in the ring structure. When more than one substituent is present on an aryl group, each substituent is independently selected. Examples of the substituent of the aryl group include alkyl, halo, haloalkyl, cyano, nitro, amino, monoalkylamino, dialkylamino, —OR ^a (wherein R ^a is hydrogen or alkyl) and the like. However, it is not limited to these.

“Aralkyl” refers to a moiety of the formula —R ^b R ^{c where} R ^b is an alkylene and R ^c is an aryl group as defined herein. Examples of aralkyl groups include, but are not limited to, benzyl, phenylethyl, and the like.

“Cycloalkyl” refers to a non-aromatic, typically saturated monovalent monocyclic or bicyclic hydrocarbon moiety of 3 to 10 ring carbons. Cycloalkyls may be optionally substituted with one or more substituents. When substituted, the cycloalkyl typically contains 1, 2, or 3 substituents within the ring structure. When more than one substituent is present on a cycloalkyl group, each substituent is independently selected. Cycloalkyls can also include one or more unsaturated (eg, olefin and / or acetylene) moieties. Examples of cycloalkyl include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cyclooctyl group, and the like. Examples of substituents for the cycloalkyl group include, but are not limited to, alkyl, haloalkyl, halo, heteroalkyl, aryl, —OR ^a (wherein R ^a is hydrogen or alkyl), and the like.

The terms “cycloalkylalkyl” and “(cycloalkyl) alkyl” are used interchangeably herein and have the formula —R ^d R ^e moiety where R ^d is an alkylene group and R ^e is as defined herein. A cycloalkyl group as defined by Examples of cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclohexylpropyl, 3-cyclohexyl-2-methylpropyl, cyclohexylmethyl, and the like.

The term “fluorohydrogenate ionic liquid” refers to an ionic liquid comprising one or more fluorohydrogenate anions. Typically, fluorohydrocarbon oxygenate anions F ^- · 2HF or F ^- · 3HF form, that is, one or more, fluoride anions solvated by customary 2 or 3 hydrogen fluoride. Typically, fluorohydrogenate ionic liquids have a melting point of less than 100 ° C. and are often liquid at room temperature. Fluorohydrocarbon oxygenate ionic liquids are typically a vacuum stable, empirical formula F ^- also taking · 2.3HF. A typical member of the fluorohydrogenate ionic liquid group comprises a quaternary ammonium cation. Often the quaternary ammonium cation comprises a nitrogen-heteroaryl cation. Examples of fluorohydrogenate ionic liquids include N-methyl-N-butylpyrrolidinium fluorohydrogenate (“PYR ₁₄ F (HF) _2.3 ”), N-methyl-N-propylpyrrolidinium fluorohydrogen Nate (“PYR ₁₃ F (HF) _2.3 ”) and N-ethyl-N-methylimidazolium fluorohydrogenate (“EMIMF (HF) _2.3 ”).

  The terms “halo”, “halogen” and “halide” are used interchangeably herein and refer to fluoro, chloro, bromo or iodo.

“Haloalkyl” refers to an alkyl group, as defined herein, in which one or more hydrogen atoms have been replaced with the same or different halo atoms. The term “haloalkyl” also includes perhalogenated alkyl groups in which all alkyl hydrogen atoms have been replaced with halogen atoms. Examples of haloalkyl groups include, but are not limited to, —CH ₂ Cl, —CF ₃ , —CH ₂ CF ₃ , —CH ₂ CCl _{3 and the} like.

“Heterocycloalkyl” is a heteroatom in which one or two ring atoms are selected from N, O or S (O) _n , where n is an integer from 0 to 2, and the remaining rings Means a non-aromatic monocyclic moiety of 3 to 8 ring atoms, wherein the atom is C and one or two C atoms may optionally be a carbonyl group. Heterocycloalkyl rings are independently optionally substituted with one or more substituents. When more than one substituent is present on a heterocycloalkyl group, each substituent is independently selected. Examples of the substituent of the heterocyclyl group include, but are not limited to, alkyl, haloalkyl, heteroalkyl, halo, aryl and the like.

The term “(heterocycloalkyl) alkyl” refers to a moiety of the formula —R ^f R ^{g where} R ^f is alkylene and R ^g is heterocycloalkyl as defined herein. .

  The term “heteroaryl” refers to one of 5 to 12 ring atoms containing 1, 2 or 3 ring heteroatoms selected from N, O or S and the remaining ring atoms being C. Refers to a monovalent or bicyclic aromatic moiety having a valence. Heteroaryl rings are independently optionally substituted with one or more substituents. Examples of heteroaryl substituents include aryl groups. Examples of heteroaryl include pyridyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, Examples include, but are not limited to, isoindolyl, benzoxazolyl, quinolyl, isoquinolyl, benzimidazolyl, benzisoxazolyl, benzothiophenyl, dibenzofuran and benzodiazepin-2-one-5-yl.

The term “heteroaralkyl” refers to a moiety of the formula —R ^h R ^{i where} R ^h is alkylene and R ⁱ is heteroaryl as defined herein.

As used herein, the term “heteroalkyl” refers to carbon, hydrogen, one or more heteroatoms instead of carbon atoms, or optionally ═O, —OR ^a , — Independently selected from C (O) R ^a , —NR ^b R ^c , —C (O) NR ^b R ^c, and —S (O) nR ^d , where n is an integer from 0 to 2. Means a branched or unbranched cyclic or acyclic saturated alkyl moiety containing one or more heteroatom-containing substituents. R ^a is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl or acyl. R ^b is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl or acyl. R ^c is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, acyl, alkylsulfonyl, carboxamide, or mono- or di-alkylcarbamoyl. Optionally, R ^b and R ^c are combined with the nitrogen to which each is attached to form a 4-membered, 5-membered, 6-membered or 7-membered heterocyclic ring (eg, a pyrrolidinyl ring, piperidinyl ring or morpholinyl ring). R ^d is hydrogen (where n is 0), alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, amino, monosubstituted amino , Disubstituted amino or hydroxyalkyl. Representative examples include 2-methoxyethyl, benzyloxymethyl, thiophen-2-ylthiomethyl, 2-hydroxyethyl and 2,3-dihydroxypropyl.

“Protecting group” refers to a moiety, excluding alkyl groups, that reduces or prevents reactivity when attached to a reactive group in a molecular mask. Examples of protecting groups, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons, New York, 1999, and Harrison and Harrison et al., Compendium of Synthetic OrganicMethods, Vols. 1-8 (John Wiley and Sons, 1971-1996), which is hereby incorporated by reference in its entirety. Representative hydroxy protecting groups include acyl groups, benzyl ethers and trityl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers. Typical amino protecting groups include formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trimethylsilyl (TMS), 2-trimethylsilyl-ethanesulfonyl (SES), trityl. Groups and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC), nitro-veratryloxycarbonyl (NVOC) and the like.

  In describing chemical reactions, the terms “treating”, “contacting”, and “reacting” are used interchangeably herein to indicate the conditions indicated and / or suitable for producing the desired product. Refers to the addition or mixing of two or more reagents below. The reaction shown and / or producing the desired product may not necessarily result directly from the combination of the two reagents initially added, i.e. finalizing the formation of the shown and / or desired product. It is to be understood that there may be one or more intermediates produced in the resulting mixture.

  As used herein, the terms “as defined above” and “as defined herein”, when referring to a variable, refer to a broad definition of that variable by reference, as well as to the variable. Including any narrow and / or narrower definitions.

Methods and Processes of the Present Invention Nucleophilic perfluoroalkylation reactions of organic compounds using perfluoroalkyltrimethylsilane are excellent methods for introducing perfluoroalkyl groups. The bond between Si and C _n F _{2n + 1 in} perfluoroalkyltrimethylsilane (Me ₃ Si—C _n F _{2n + 1} ) is weak due to the high electron withdrawing property of the perfluoroalkyl group. The bond is easily cleaved by fluoride ions to produce Me ₃ SiF, and a perfluoroalkyl anion (ie, C _n F _{2n + 1} ⁻ ) is liberated as a nucleophile.

  Unfortunately, conventional methods of introducing perfluoroalkyl groups using perfluoroalkyltrimethylsilane as described above are relatively slow or slow processes or result in low yields of desired products. There are many. In particular, conventional catalysts and / or initiators are hygroscopic, making conventional methods unsuitable in many cases.

  The inventors have discovered that many of the deficiencies of the conventional method of introducing perfluoroalkyl groups can be easily overcome by using a fluorohydrogenate ionic liquid. A wide variety of compounds can be perfluoroalkylated using the method of the present invention. Some of the compounds that can be perfluoroalkylated include carbonyl compounds (ie, compounds containing a C═O functional group), such as ketones, aldehydes and esters, and sulfonic acid compounds, sulfinic acid compounds and selenic acid compounds. It is.

スキーム1

更にスキーム1を参照して、この反応では通例、シリルエーテル中間体が生成される。このシリルエーテルは、単離するか又はin situで若しくは検査（work-up）プロセス中に対応するアルコール若しくはケトンに転化することができる。 In some embodiments, as shown in Scheme 1, the present invention provides a simple one-step process for perfluoroalkylating carbonyl compounds such as esters, aldehydes and ketones. Fluorohydrogenate ionic liquids such as EMIMF (HF) _2.3 , PYR ₁₄ F (HF) _2.3 , PYR ₁₃ F (HF) _2.3 or combinations thereof in the presence of a carbonyl compound and a general formula (CH ₃ ) ₃ Si-C _It is customary to react with _n F _{2n + 1} perfluoroalkyltrimethylsilane. In many cases, a fluorohydrogen ionic liquid is used as a catalyst. The typical amount of fluorohydrogen ionic liquid used in the process of the present invention is less than 1 equivalent, often about 0.5 equivalents or less, more often about 0.2 equivalents to 0.4 equivalents, relative to the amount of carbonyl compound. Most often less than about 0.1 equivalents.

Scheme 1

Still referring to Scheme 1, this reaction typically produces a silyl ether intermediate. The silyl ether can be isolated or converted into the corresponding alcohol or ketone in situ or during the work-up process.

The carbonyl compound is an aldehyde, such as RCHO where R is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, haloalkyl, heteroalkyl, (cycloalkyl) alkyl, (heterocycloalkyl) alkyl, aralkyl or When it is heteroaralkyl, the product produced by the process of the present invention is of the formula R (C _n F _{2n + 1} ) CH (OR ′), where n is typically an integer from 1 to 8 R ′ is hydrogen or a trialkylyl group such as trimethylsilyl) or a perfluoroalkylated silyl ether or alcohol.

The carbonyl compound is a ketone, such as R′COR ″ where R ′ and R ″ are each independently alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, haloalkyl, heteroalkyl, (cycloalkyl) Alkyl, (heterocycloalkyl) alkyl, aralkyl or heteroaralkyl), the resulting product is of the formula R ′ (C _n F _{2n + 1} ) CR ″ (OR) where n is typically It is an integer from 1 to 8, and R is hydrogen or a trialkylylsilyl group such as trimethylsilyl) or a corresponding alcohol.

The carbonyl compound is an ester such as RCO ₂ R ′ (wherein R is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, haloalkyl, heteroalkyl, (cycloalkyl) alkyl, (heterocycloalkyl) alkyl, Aralkyl or heteroaralkyl and R ′ is alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, haloalkyl, heteroalkyl, (cycloalkyl) alkyl, (heterocycloalkyl) alkyl, aralkyl or heteroaralkyl) in some cases, (wherein, n usually a is an integer of 1 to 8) equation resulting intermediate _{R (C n F 2n + 1} ) C = O can be converted into the corresponding perfluoroalkyl ketone compounds .

The carbonyl compound may contain other functional group (s) as long as it is relatively non-reactive under the reaction conditions or is protected. For example, an aminoester such as R ₂ N (CH ₂ ) _m CO ₂ R ′ (wherein each R is alkyl or aryl, m is an integer from 1 to 6, R ′ is alkyl, cycloalkyl, Cycloalkyl, aryl, heteroaryl, haloalkyl, heteroalkyl, (cycloalkyl) alkyl, (heterocycloalkyl) alkyl, aralkyl or heteroaralkyl) can be represented by the formula R ₂ N (CH ₂ ) _m (C _n F _{2n + 1} ) C = O, where n is typically an integer from 1 to 8, can be converted to the corresponding perfluoroalkylated compound.

Other compounds that can be perfluoroalkylated include sulfonate esters (eg, R′—SO ₂ —OR ″), sulfinate esters (eg, R′—SO—OR ″), and selenate esters. (Eg, R′-SeO-OR ″) wherein R ′ is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, haloalkyl, heteroalkyl, (cycloalkyl) alkyl, (heterocycloalkyl ) Alkyl, aralkyl or heteroaralkyl, where R ″ is alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, haloalkyl, heteroalkyl, (cycloalkyl) alkyl, (heterocycloalkyl) alkyl, aralkyl or heteroaralkyl Is). Typically, R ′ is alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, haloalkyl, heteroalkyl, (cycloalkyl) alkyl, (heterocycloalkyl) alkyl, aralkyl or heteroaralkyl). The resulting products of these compounds are respectively the formulas R-SO ₂ (C _n F _{2n + 1} ), RS (O)-(C _n F _{2n + 1} ) and R-Se (O)-(C _n F _{2n + 1} ) where n is typically an integer from 1 to 8.

  The reaction temperature is the reactivity of the carbonyl (or sulfonic acid, sulfinic acid or selenic acid) compound, the amount of perfluoroalkylated silane compound used, the amount and nature of the fluorohydrogenate ionic liquid used, the solvent used , Reaction time, etc., but may vary depending on a variety of factors not limited to these. However, typical reaction temperatures range from about −78 ° C. to about 50 ° C., typically from about −40 ° C. to about 30 ° C., and often from about −10 ° C. to about 25 ° C. In general, the reaction is carried out at 0 ° C. to room temperature.

  The yield of silyl ether intermediate or final product can also vary depending on a wide variety of factors such as those described above. Typically, the product yield is at least 80%, often at least 90%, more often at least 95%. Such a yield is significantly higher than the conventional method.

  The reaction time can vary greatly depending on various factors such as those described above. In addition, the concentration of reactants can also affect the reaction time. Typically, however, the reaction time ranges from about 1 hour to about 24 hours, often from about 1 hour to about 12 hours, and more often from about 1 hour to about 6 hours.

  When perfluoroalkyltrimethylsilane is used as the perfluoroalkylated compound, the reaction also produces trimethylsilyl fluoride. This product can be recovered and reused.

  The usefulness of organic compounds containing perfluoroalkyl groups is known to those skilled in the art. For example, trifluoromethyl ketone is known as a potent inhibitor of hydrolases because it can form stable hydrates (Gelb, Svaren, and Abeles 1985). Prior to the discovery by the inventors, the typical method for the synthesis of trifluoromethyl ketone was not widely known and involved multi-step synthetic operations (Begue and Bonnet-Delpon 1991) (Yokoyama and Mochida 1997 Keumi et al. 1990, Cockburn and Bannard 1957).

  Further objects, advantages and novel features of the present invention will become apparent to those skilled in the art upon examination of the following examples, which are not intended to be limiting. In the embodiment, the method that is actively carried out is described in the present tense, and the method performed in the laboratory is described in the past tense.

  All reactions were performed under an anhydrous argon atmosphere. All fluorohydrogenate ionic liquids used herein were synthesized by using anhydrous HF under anhydrous conditions.

無水ベンズアルデヒド（1.06 mg、10 mmol）及び（トリフルオロメチル）トリメチル−シラン（1.46 g、10.25 mmol）を、アルゴン下において乾燥フラスコに入れ、10 mlのジクロロメタンに溶解した。得られた溶液を、氷水浴を用いて冷却した。反応混合物を撹拌しながら、触媒量のEMIM F(HF)_2.3（35 mg、0.2 mmol）を添加した。幾らかのガスの発生（Me₃SiF）が観察された。0.5時間の撹拌後、氷水浴を取り外し、更に2.5時間、室温にて撹拌した。次いで反応混合物を、4 N塩酸（10 ml）を用いてクエンチし、室温にて1時間撹拌した。得られた溶液を別の5 mlのジクロロメタンにて希釈して、水相を除去した。有機層を10 mlの水で洗浄し、濃縮することで、所望の生成物を得た（収量：1.62 g、収率：92 %）。CDCl₃におけるフッ素のnmrは、CF₃に割り当てられた-76.6 ppmでのダブレットを示し、J_F-H=7.0 Hzであった。 Example 1

Anhydrous benzaldehyde (1.06 mg, 10 mmol) and (trifluoromethyl) trimethyl-silane (1.46 g, 10.25 mmol) were placed in a dry flask under argon and dissolved in 10 ml of dichloromethane. The resulting solution was cooled using an ice water bath. While stirring the reaction mixture, a catalytic amount of EMIM F (HF) _2.3 (35 mg, 0.2 mmol) was added. Some gas evolution (Me ₃ SiF) was observed. After stirring for 0.5 hour, the ice-water bath was removed and the mixture was further stirred for 2.5 hours at room temperature. The reaction mixture was then quenched with 4 N hydrochloric acid (10 ml) and stirred at room temperature for 1 hour. The resulting solution was diluted with another 5 ml of dichloromethane to remove the aqueous phase. The organic layer was washed with 10 ml of water and concentrated to give the desired product (yield: 1.62 g, yield: 92%). The fluorine nmr in CDCl ₃ showed a doublet at -76.6 ppm assigned to CF ₃ with J _FH = 7.0 Hz.

無水ベンズアルデヒド（1.06 mg、10 mmol）及び（トリフルオロメチル）トリメチル−シラン（1.46 g、10.25 mmol）を、アルゴン下において乾燥フラスコに入れ、10 mlのジクロロメタンに溶解した。得られた溶液を、氷水浴を用いて冷却した。触媒量のメチルブチルピロリジニウムフルオロハイドロジェネート（「PYR₁₄F(HF)_2.3」）（41.4 mg、0.2 mmol）を混合物に添加した。幾らかのガスの発生（Me₃SiF）が見られた。0.5時間の撹拌後、氷水浴を取り外し、混合物を更に2.5時間、室温にて撹拌した。次いで反応を、4 N塩酸（10 ml）を用いて停止させ、室温にて1時間撹拌した。得られた混合物を5 mlのジクロロメタンにて希釈して、水相を除去した。有機層を10 mlの水で洗浄し、濃縮することで、所望の生成物を得た（収量：1.58 g、収率：90 %）。CDCl₃におけるフッ素のnmrは、CF₃に割り当てられた-76.6 ppmでのダブレットを示し、J_F-H=7.0 Hzであった。 Example 2

Anhydrous benzaldehyde (1.06 mg, 10 mmol) and (trifluoromethyl) trimethyl-silane (1.46 g, 10.25 mmol) were placed in a dry flask under argon and dissolved in 10 ml of dichloromethane. The resulting solution was cooled using an ice water bath. A catalytic amount of methylbutylpyrrolidinium fluorohydrogenate (“PYR ₁₄ F (HF) _2.3 ”) (41.4 mg, 0.2 mmol) was added to the mixture. Some gas evolution (Me ₃ SiF) was observed. After 0.5 hours of stirring, the ice-water bath was removed and the mixture was stirred for an additional 2.5 hours at room temperature. The reaction was then quenched with 4N hydrochloric acid (10 ml) and stirred at room temperature for 1 hour. The resulting mixture was diluted with 5 ml of dichloromethane to remove the aqueous phase. The organic layer was washed with 10 ml of water and concentrated to give the desired product (yield: 1.58 g, yield: 90%). The fluorine nmr in CDCl ₃ showed a doublet at -76.6 ppm assigned to CF ₃ with J _FH = 7.0 Hz.

無水アセトフェノン（1.20 g、10 mmol）及び（トリフルオロメチル）トリメチルシラン（1.46 g、10.25 mmol）をアルゴン下において乾燥フラスコに入れ、10 mlのジクロロメタンに溶解した。混合物を、氷水浴を用いて冷却した。触媒量のEMIMF(HF)_2.3（35 mg、0.2 mmol）を添加した。幾らかのガスの発生（Me₃SiF）が見られた。0.5時間の撹拌後、氷水浴を取り外し、混合物を更に2.5時間、室温にて撹拌した。反応を、4 N塩酸（10 ml）を添加することで停止させ、得られた溶液を室温にて1時間撹拌し、5 mlのジクロロメタンにて希釈した。水相を除去した。有機層を10 mlの水で洗浄し、濃縮することで、所望の生成物を得た（収量：1.78 g、収率：94 %）。CDCl₃におけるフッ素のnmrは、CF₃に割り当てられた-81.7 ppmでのシングレットを示した。 Example 3

Anhydrous acetophenone (1.20 g, 10 mmol) and (trifluoromethyl) trimethylsilane (1.46 g, 10.25 mmol) were placed in a dry flask under argon and dissolved in 10 ml of dichloromethane. The mixture was cooled using an ice water bath. A catalytic amount of EMIMF (HF) _2.3 (35 mg, 0.2 mmol) was added. Some gas evolution (Me ₃ SiF) was observed. After 0.5 hours of stirring, the ice-water bath was removed and the mixture was stirred for an additional 2.5 hours at room temperature. The reaction was stopped by adding 4 N hydrochloric acid (10 ml) and the resulting solution was stirred at room temperature for 1 hour and diluted with 5 ml of dichloromethane. The aqueous phase was removed. The organic layer was washed with 10 ml of water and concentrated to give the desired product (yield: 1.78 g, yield: 94%). The fluorine nmr in CDCl ₃ showed a singlet at -81.7 ppm assigned to CF ₃ .

無水アセトフェノン（1.20 g、10 mmol）及び（トリフルオロメチル）トリメチルシラン（1.46 g、10.25 mmol）をアルゴン下において乾燥フラスコに入れ、10 mlのジクロロメタンに溶解した。得られた溶液を、氷水浴を用いて冷却した。触媒量のPYR₁₃F(HF)_2.3（38 mg、0.2 mmol）を添加した。幾らかのガスの発生（Me₃SiF）が見られた。0.5時間の撹拌後、氷水浴を取り外し、混合物を更に2.5時間、室温にて撹拌した。反応を、4 N塩酸（10 ml）を添加することで停止させ、得られた溶液を室温にて1時間撹拌し、5 mlのジクロロメタンにて希釈した。水相を除去した。有機層を10 mlの水で洗浄し、濃縮することで、所望の生成物を得た（収量：1.72 g、収率：91 %）。CDCl₃におけるフッ素のnmrは、CF₃に割り当てられた-81.7 ppmでのシングレットを示した。 Example 4

Anhydrous acetophenone (1.20 g, 10 mmol) and (trifluoromethyl) trimethylsilane (1.46 g, 10.25 mmol) were placed in a dry flask under argon and dissolved in 10 ml of dichloromethane. The resulting solution was cooled using an ice water bath. A catalytic amount of PYR ₁₃ F (HF) _2.3 (38 mg, 0.2 mmol) was added. Some gas evolution (Me ₃ SiF) was observed. After 0.5 hours of stirring, the ice-water bath was removed and the mixture was stirred for an additional 2.5 hours at room temperature. The reaction was stopped by adding 4 N hydrochloric acid (10 ml) and the resulting solution was stirred at room temperature for 1 hour and diluted with 5 ml of dichloromethane. The aqueous phase was removed. The organic layer was washed with 10 ml of water and concentrated to give the desired product (yield: 1.72 g, yield: 91%). The fluorine nmr in CDCl ₃ showed a singlet at -81.7 ppm assigned to CF ₃ .

無水エチルヒドロシンナメート（1.78 g、10 mmol）及び（トリフルオロメチル）トリメチルシラン（1.46 g、10.25 mmol）をアルゴン下において乾燥フラスコに入れ、10 mlのジクロロメタンに溶解した。得られた溶液を、氷水浴を用いて冷却した。触媒量のEMIMF(HF)_2.3（35 mg、0.2 mmol）を添加した。幾らかのガスの発生（Me₃SiF）が見られた。0.5時間の撹拌後、氷水浴を取り外し、混合物を更に5時間、室温にて撹拌した。反応を、4 N塩酸（10 ml）を添加することで停止させ、得られた混合物を室温にて1時間撹拌した。混合物を5 mlのジクロロメタンにて希釈し、水相を除去した。有機層を10 mlの水で洗浄し、濃縮することで、所望の生成物を得た（収量：1.76 g、収率：87 %）。CDCl₃におけるフッ素のnmrは、CF₃に割り当てられた-80.2 ppmでのシングレットを示した。 Example 5

Anhydrous ethylhydrocinnamate (1.78 g, 10 mmol) and (trifluoromethyl) trimethylsilane (1.46 g, 10.25 mmol) were placed in a dry flask under argon and dissolved in 10 ml of dichloromethane. The resulting solution was cooled using an ice water bath. A catalytic amount of EMIMF (HF) _2.3 (35 mg, 0.2 mmol) was added. Some gas evolution (Me ₃ SiF) was observed. After 0.5 hours of stirring, the ice water bath was removed and the mixture was stirred for an additional 5 hours at room temperature. The reaction was stopped by adding 4 N hydrochloric acid (10 ml) and the resulting mixture was stirred at room temperature for 1 hour. The mixture was diluted with 5 ml dichloromethane and the aqueous phase was removed. The organic layer was washed with 10 ml of water and concentrated to give the desired product (yield: 1.76 g, yield: 87%). The fluorine nmr in CDCl ₃ showed a singlet at -80.2 ppm assigned to CF ₃ .

無水エチルヒドロシンナメート（1.78 g、10 mmol）及び（トリフルオロメチル）トリメチルシラン（1.46 g、10.25 mmol）をアルゴン下において乾燥フラスコに入れ、10 mlのジクロロメタンに溶解した。得られた混合物を、氷水浴を用いて冷却し、触媒量のPYR₁₄F(HF)_2.3（41.4 mg、0.2 mmol）を添加した。幾らかのガスの発生（Me₃SiF）が見られた。0.5時間の撹拌後、氷水浴を取り外し、混合物を更に5時間、室温にて撹拌した。反応を、4 N塩酸（10 ml）を添加することで停止させ、得られた混合物を室温にて1時間撹拌した。溶液を5 mlのジクロロメタンにて希釈し、水相を除去した。有機層を10 mlの水で洗浄し、濃縮することで、所望の生成物を得た（収量：1.78 g、収率：88 %）。CDCl₃におけるフッ素のnmrは、CF₃に割り当てられた-80.2 ppmでのシングレットを示した。 Example 6

Anhydrous ethylhydrocinnamate (1.78 g, 10 mmol) and (trifluoromethyl) trimethylsilane (1.46 g, 10.25 mmol) were placed in a dry flask under argon and dissolved in 10 ml of dichloromethane. The resulting mixture was cooled using an ice water bath and a catalytic amount of PYR ₁₄ F (HF) _2.3 (41.4 mg, 0.2 mmol) was added. Some gas evolution (Me ₃ SiF) was observed. After 0.5 hours of stirring, the ice water bath was removed and the mixture was stirred for an additional 5 hours at room temperature. The reaction was stopped by adding 4 N hydrochloric acid (10 ml) and the resulting mixture was stirred at room temperature for 1 hour. The solution was diluted with 5 ml dichloromethane and the aqueous phase was removed. The organic layer was washed with 10 ml of water and concentrated to give the desired product (yield: 1.78 g, yield: 88%). The fluorine nmr in CDCl ₃ showed a singlet at -80.2 ppm assigned to CF ₃ .

  The foregoing description of the present invention has been presented for purposes of illustration and description. The above description is not intended to limit the invention to the form or forms disclosed herein. The description of the invention includes a description of one or more embodiments and several variations and modifications, such as may be within the skill and knowledge of those skilled in the art after understanding the present disclosure. Other variations and modifications are within the scope of the present invention. The right to include alternative embodiments to the extent permitted, including alternative, interchangeable and / or equivalent structures, functions, ranges or steps to those claimed, such alternatives Intended to obtain any patentable subject matter without intent to dedicate to the public, regardless of whether or not interchangeable and / or equivalent structures, functions, ranges or processes are disclosed herein. Is done.

Claims (23)

  A method for producing a compound comprising a fully fluorinated alkyl group moiety from a carbonyl compound, wherein the method is in the presence of a fluorohydrogenate ionic liquid under conditions sufficient to produce a compound comprising a fully fluorinated alkyl group. Contacting with a carbonyl compound and a silane compound containing a perfluoroalkyl group.   2. The method according to claim 1, wherein the carbonyl compound is an aldehyde, a ketone or an ester.   2. The method of claim 1, wherein the silane compound is a perfluoroalkyl (trialkyl) silane compound.   2. The method of claim 1, wherein the fluorohydrogen ionic liquid comprises a quaternary ammonium cation.   5. The method of claim 4, wherein the quaternary ammonium cation comprises a nitrogen-heteroaryl cation.   The quaternary ammonium cation comprises N-ethyl-N-methylimidazolium, N-methyl-N-propylpyrrolidinium, N-methyl-N-butylpyrrolidinium, or a combination thereof. The method described.   2. The method according to claim 1, wherein the amount of the fluorohydrogenate ionic liquid used in the method is less than 1 equivalent relative to the amount of the carbonyl compound. formula:

In the presence of a fluorohydrogenate ionic liquid under conditions sufficient to produce a siloxy compound of formula I:

A carbonyl compound of formula III:

Contacting with a silyl compound of
Where
n is an integer from 1 to 30,
R ¹ is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, haloalkyl, heteroalkyl, (cycloalkyl) alkyl, (heterocycloalkyl) alkyl, aralkyl or heteroaralkyl;
R ² is hydrogen, alkyl, or a moiety of the formula —OR ^{4 where} R ⁴ is alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, haloalkyl, heteroalkyl, (cycloalkyl) alkyl, (heterocycloalkyl) alkyl , Aralkyl or heteroaralkyl,
The method wherein R ³ is each independently alkyl, cycloalkyl, aryl, (cycloalkyl) alkyl or aralkyl. R ² has the formula -OR ⁴ moiety (wherein, R ⁴ is as defined in claim 8) is a method of claim 8. Hydrolysis of the siloxy compound of formula I to give the formula:

10. The method of claim 9, further comprising the step of producing a ketone compound of the formula (wherein n is as defined in claim 8). R ³ are each independently a C ₁ -C ₆ alkyl, The method of claim 8. R ³ is methyl, A method according to claim 11.   9. The method of claim 8, wherein the fluorohydrogenate ionic liquid comprises a quaternary ammonium cation.   14. The method of claim 13, wherein the quaternary ammonium cation comprises a nitrogen-heteroaryl cation.   The quaternary ammonium cation comprises N-ethyl-N-methylimidazolium, N-methyl-N-propylpyrrolidinium, N-methyl-N-butylpyrrolidinium, or a combination thereof. The method described. R ² is hydrogen or alkyl, The method of claim 8. Hydrolysis of the siloxy compound of formula I to give the formula:

17. The method of claim 16, further comprising producing an alcohol compound of:   9. The method of claim 8, wherein the amount of the fluorohydrogenate ionic liquid used in the method is less than 1 equivalent relative to the amount of the carbonyl compound of formula II.   19. The method of claim 18, wherein the amount of the fluorohydrogenate ionic liquid used in the method ranges from about 0.2 equivalents to 0.4 equivalents relative to the amount of the carbonyl compound of formula II.   9. The method of claim 8, wherein the amount of the silyl compound of formula III used in the method is at least 1 equivalent relative to the amount of the carbonyl compound of formula II.   9. A process according to claim 8, wherein the reaction is carried out in the absence of any other catalyst.   A method for producing a compound comprising a fully fluorinated alkyl group moiety from a carbonyl compound, wherein the method is in the presence of a fluorohydrogenate ionic liquid under conditions sufficient to produce a compound comprising a fully fluorinated alkyl group. Consisting essentially of contacting a carbonyl compound with a silane compound containing a perfluoroalkyl group at   A method for producing a compound comprising a fully fluorinated alkyl group moiety from a carbonyl compound, wherein the method is in the presence of a fluorohydrogenate ionic liquid under conditions sufficient to produce a compound comprising a fully fluorinated alkyl group. Contacting the carbonyl compound with a silane compound containing a perfluoroalkyl group at a step, wherein the amount of the fluorohydrogenate ionic liquid used in the method is less than 1 equivalent relative to the amount of the carbonyl compound .